The hypothesis to be tested in this project is that activation of TOPK and CBII2 play a functional role in solar UV signal transduction and skin carcinogenesis. Therefore, these signaling molecules can be used as targets for the development of chemopreventive agents to inhibit solar UV skin cancers. The specific aims to address the hypothesis are: Specific Aim 1. To determine the role of CB1I2 and TOPK in solar UV-induced phosphorylation of MAP kinases, including JNKs and ERKs. Specific Aim 2. To develop novel small molecule inhibitors of TOPK and test the inhibitory effect of these novel TOPK inhibitors on cell transformation. Specific Aim 3. To determine the role of CB1I2 and TOPK in solar UV-induced skin carcinogenesis by using CB1I2 gene knockout mice and TOPK gene knockout mice, respectively. We will use state-of-the-art technology including computational biological simulations on the Blue Gene/L Super Computer, knockout mouse model and other molecular biological methods to finish the proposed studies. These preclinical studies are designed to lead to the development of new strategies for the chemoprevention of human skin cancers.